Opioid antagonists have been indispensable as tools in opioid research. For example, the chief criterion for the classification of an agonist effect as being opioid receptor mediated is the ability of known opioid antagonists naloxone or naltrexone to reversibly antagonize this effect in a competitive fashion. The usefulness of naloxone and naltrexone for this purpose stems from the fact that they are universal opioid antagonists; that is, they are capable of antagonizing the agonist effects mediated by multiple opioid receptor types.
In addition to their uses as pharmacological tools, selective, non-peptide opioid antagonists have been described as having potential clinical applications in the treatment of a variety of disorders where endogenous opioids play a modulatory role. These include for instance disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, and immune function (P. S. Portoghese at al., J. Med. Chem., Vol. 34: 1757-1762, 1991).
Non-peptide, competitive, .delta.-selective opioid antagonists have been found to have immunosuppressive potency and less toxicity than the presently used immunosuppressive compound cyclosporin (EP 456 833; EP 485 636; EP 614 898; K. Arakawa et al., Transplantation, Vol. 53: 951-953, 1992; K. Arakawa et al., Transplant Proc., Vol. 24: 696-697, 1992; K. Arakawa et al., Transplant Proc., Vol. 25: 738-740, 1993). Such immunosuppressive agents can be used after organ transplantation to suppress the rejection of the foreign organ and also in the treatment of autoimmune diseases (e.g. rheumatoid arthritis).
In U.S. Pat. No. 5,223,507 and U.S. Pat. No. 5,225,417 the synthesis of 14-O-substituted indolomorphinans and benzofuranomorphinans have been disclosed. According to the process used for preparing the compounds claimed and disclosed in U.S. Pat. No. 5,223,507, only a 3,14-dimethoxy substituted benzofuranomorphinan was prepared. According to the process used for preparing compounds claimed and disclosed in U.S. Pat. No. 5,225,417, two 14-O-alkyl substituted benzofuranomorphinans have been prepared. According to the methods used for preparing the compounds of both the two mentioned prior art documents, the 3-hydroxy group was protected by a methyl group which is not easily removed without having a loss in yield.
According to the processes known from the prior art, the variations of the substituents at the oxygen in position 14 are very much limited when a 3-hydroxy group is supposed to be present in the molecule. It is for instance not possible to prepare compounds with a substituent at the oxygen in 14-position, as this position is labile to the conditions used for the cleavage of the 3-methoxy group.
Thus, the object of the present invention was to find a new process which would facilitate the preparation of 14-O-substituted indolomorphinans and benzofuranomorphinans.
The present patent application discloses a process whereby naloxone, naltrexone or oxymorphone is used as the starting material, whereby the 14-alkoxy group is introduced after the protection of the oxygen in 3-position with an easily removable protecting group, preferably benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, thereby providing a process enabling the synthesis of compounds involving 14-O-substitution.